To support development of novel therapies for Cystic Fibrosis (CF), the Cell Models Core (Core C) of the University of North Carolina (UNC) CF Research and Translation Core Center will provide multiple services and resources. These will be available to UNC CF Center members, to other local investigators, and to the national and international CF translational medicine communities. As well as our traditional strengths to provide normal and CF human and mouse airway epithelial cell air liquid interface cultures in systems reproducing important elements of the airway in vivo, we have developed capabilities to dramatically expand populations of primary epithelial cells. These methods increase the supply of primary epithelial cells from the airway, distal lung and GI tract, and will facilitate personalizing therapies for CF individuals via studies of cells from small, minimally invasive specimens. We illustrate Ussing chamber studies of planar GI cell preparations, and unique 3D spheroid cultures including nasospheres, bronchospheres and gut organoids with characteristic CF and non-CF properties. We support overexpression, shRNA, CRISPR-Cas9, and oligonucleotide genetic manipulation of primary cells for mechanistic studies. The Core observes the philosophy of developing non- proprietary technology and supporting its widespread translation locally, nationally and internationally via both training and provision of cell procurement and characterization services to outside suppliers of tissue specimens. The interaction of the Cell Models Core with the other Cores in this proposal will facilitate rapid, rigorous and reproducible research and pre-clinical testing necessary to overcome the significant barriers to bench to bedside translation of novel CF therapies and personalized testing.